It has been estimated that in persons between the ages of 35 and 64 years of age, nearly 1 death in three is due to coronary heart disease Gordon, T.; Kannel, W. B. J. Amer. Med. Assoc., 1971, 215,1617] and there are approximately 400,000 sudden cardiac deaths annually in the United States alone [Green, H. L.; et al, Amer. J. Cardiology, 1989, 63, 1]. Over the last few years, development of drugs to treat cardiac arrhythmias (sudden cardiac death) has received much attention [Steinberg, M. I.; Lacefield, W. B.; Robertson, D. W. Class I and III Antiarrhythmic Drugs. In Ann. Reports in Med. Chem., Bailey, D. M., Ed.; Academic Press, Inc.: Orlando, 1986; 21, pp 95-108; Arrowsmith, J. E.; Cross, P. E. Antiarrhythmic Agents. In Ann. Reports in Med. Chem., Bristol, J. A., Ed.; Academic Press, Inc.: San Diego, 1990; 25, pp 79-88]. A classification of these drugs has been presented by Vaughan Williams [Vaughan Williams, E. M. J. Clin. Pharmacol., 1984, 24, 129] which is based on their electrophysiological effects on cardiac tissue.
Class I agents and subclasses (Ia, Ib, Ic) are defined as antiarrhythmic agents which have inhibitory effects on the sodium channel which result in a reduction of conduction velocity in the cardiac tissue . The Class I agents are currently the most widely used for antiarrhythmic therapy. Recent results of the Cardiac Arrhythmia Suppression Trial (CAST), [N. Engl. J. Med., 1989, 321, 4061, have raised concerns about the Class IC subtype (e.g. flecainide) and suggest that antiarrhythmic drugs having other mechanisms of action should be considered.
Specific Class III antiarrhythmic drugs (e.g. d-sotalol) do not affect cardiac sodium channels or conduction velocity. These agents selectively prolong the cardiac action potential duration and thereby increase the effective refractory period (ERP). Prolongation of refractoriness is an effective means of preventing or terminating atrial and ventricular arrhythmias, the latter of which can be life threatening.
The discovery and development of new Class III antiarrhythmic agents which may be effective for the prevention of sudden cardiac death is desirable and is an object of the present invention.
It is therefore an object of the invention to provide novel compounds which are useful as antiarrhythmic agents. Additional objects and advantages of the invention will be set forth, in part, in the description which follows and in part will be obvious from this description, or may be learned by practice of the invention. The objects and advantages of the invention are realized and obtained by means of the methods, and the combinations particularly pointed out in the appended claims.